US12168009B2ActiveUtilityA1
Modulators of cystic fibrosis transmembrane conductance regulator
Est. expiryOct 6, 2034(~8.2 yrs left)· nominal 20-yr term from priority
Inventors:Mark MillerCorey AndersonVijayalaksmi ArumugamBrian BearHayley BinchJeremy J. ClemensThomas ClevelandErica ConroyTimothy Richard CoonBryan A. FriemanPeter Diederik Jan GrootenhuisRaymond Stanley GrossSara Sabina Hadida-RuahHaripada KhatuyaPramod JoshiPaul KrenitskyChun-Chieh LinGulin Erdogan MareliusVito MelilloJason MccartneyGeorgia Mcgaughey NichollsFabrice PierreAlina SilinaAndreas P. TerminJohnny UyJinglan Zhou
C07D 213/64C07D 209/49C07D 209/18C07D 407/12C07D 239/34C07D 403/10C07D 235/24C07D 401/04C07D 231/20C07D 213/73C07D 413/14C07D 403/12A61J 1/035A61K 31/4525A61K 31/496A61K 31/4709A61K 31/4545C07D 405/14C07D 417/12A61K 31/497C07D 231/12C07D 401/14A61K 31/4439C07D 401/12A61K 31/404C07D 209/42A61K 31/415C07D 231/14C07D 213/84A61K 31/44A61K 31/444A61K 31/4418C07D 213/82A61P 43/00A61P 11/00A61K 31/47A61K 31/36Y02A50/30A61K 31/506
93
PatentIndex Score
1
Cited by
400
References
46
Claims
Abstract
The present invention features a compound of formula I: or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , W, X, Y, Z, n, o, p, and q are defined herein, for the treatment of CFTR mediated diseases, such as cystic fibrosis. The present invention also features pharmaceutical compositions, method of treating, and kits thereof.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A compound of formula Ia:
a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, independently for each occurrence:
Ring B is a C6-C10 aryl ring or C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR;
Ring C is a C6-C10 aryl ring, C3-C14 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently N, O, or S, or a C3-C10 cycloalkyl ring;
X is O or NR;
Y is CRR, CO, O, S, SO, SO 2 , S(O)NH or NR;
R 1 is halo; CN; F 5 S; SiR 3 ; OH; NRR; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; C2-C6 alkenyl; C2-C6 alkynyl; (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR; C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
R 2 is halo; OH; NRR; azide; CN; CO 2 R; C1-C6 alkyl; C1-C6 fluoroalkyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; C2-C6 alkenyl; C2-C6 alkynyl; C6-C10 aryl; C3-C13 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 2 may form a ═CH 2 or ═O group;
R 3 is halo; CN; CO 2 R; C1-C6 alkyl; C1-C6 fluoroalkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C6 alkoxy; C1-C6 fluoroalkoxy; or C6-C10 aryl; C3-C10 heteroaryl or heterocyclic ring wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; or a (C1-C9 alkylene)-R 4 wherein up to four CH 2 units are independently replaced with O, CO, S, SO, SO 2 or NR;
or two R 3 may form a ═CH 2 or ═O group;
R 4 is H; azide; CF 3 ; CHF 2 ; OR; CCH; CO 2 R; OH; C6-C10 aryl, C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; C3-C10 cycloalkyl; NRR, NRCOR, CONRR, CN, halo, or SO 2 R;
R is independently H; OH; CO 2 H; CO 2 ; C1-C6 alkyl; C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C6-C10 aryl; C3-C10 heteroaryl or heterocycloalkyl wherein anywhere from 1 to 4 ring atoms are independently O, S, N, or NR; or C3-C10 cycloalkyl;
n is 0, 1, 2 or 3;
o is 0, 1, 2, 3, 4, or 5;
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.
2. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is phenyl, pyridyl, pyridine-2 (1H)-one, pyrazole, indole, thiophene, dihydrobenzofuran, pyrazine, indazole, thiazole, pyridine-4 (1H)-one, pyrrolidinone, or quinoline.
3. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is selected from
4. The compound, deuterated derivative, or salt of claim 1 , wherein ring C is phenyl, indole, cycloalkyl, pyridyl, pyrrolidine, naphthalene, piperidine, or dihydroindene.
5. The compound, deuterated derivative, or salt of claim 1 , wherein ring C is
6. The compound, deuterated derivative, or salt of claim 1 , wherein Y is O.
7. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH 2 .
8. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(C1-C6 alkyl).
9. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(CH 3 ).
10. The compound, deuterated derivative, or salt of claim 1 , wherein Y is CH(CH 2 CH 3 ).
11. The compound, deuterated derivative, or salt of claim 1 , wherein R 1 is halo, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or a phenyl, pyridyl, pyrimidine, indole, aza-indole, or thiophene ring, wherein all rings may be substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl, C1-C6 fluoroalkoxy, OH, CH 2 OH, CH 2 OCH 3 , CN, CO 2 H, amino, amido, C3-C10 heteroaryl, C3-C10 heterocycloalkyl, or a (C1-C8 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.
12. The compound, deuterated derivative, or salt of claim 1 , wherein R 1 is selected from CH 3 , Cl, F, CN, OCH 3 , CF 3 , CH 2 CH 3 , tBu, CH(CH 3 ) 2 ,
13. The compound, deuterated derivative, or salt of claim 1 , wherein R 2 is halo, OH, CN, azide, amino, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, C3-C10 mono- or bicyclic heterocyclic ring wherein up to 4 carbon atoms may be replaced with O, S, N, or NR; or a (C1-C8 alkyl)-R 4 wherein up to three CH 2 units may be replaced with O, CO, S, SO, SO 2 or NR.
14. The compound, deuterated derivative, or salt of claim 1 , wherein R 2 is selected from Cl, F, OH, CN, N 3 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CH 3 , CH 2 OH, CH 2 CH 3 , CH(CH 3 ) 2 , CHF 2 , OCH 3 , OCF 3 , OCHF 2 , OCH(CH 3 ) 2 , C(O)CH 3 , CH 2 CH 2 OH, CH 2 NH 2 , NH(CH 2 ) 2 OH, NH(CH 2 ) 2 N(CH 3 ) 2 , NH(CH 2 ) 2 NH 2 , NH(CH 2 ) 3 NH 2 , NH(CH 2 ) 2 OCH 3 , NHCH(CH 3 ) 2 ,
and CO 2 H.
15. The compound, deuterated derivative, or salt of claim 1 , wherein R 3 is selected from halo, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, and C3-C10 mono- or bicyclic heteroaryl wherein up to 4 carbon atoms may be replaced by O, S, N, or NR.
16. The compound, deuterated derivative, or salt of claim 1 , wherein R 3 is selected from Cl, F, CN, CH 3 , OCH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 CH 2 CH 3 , OCH 2 CH 3 , CH 2 OCH 3 , CH(CH 3 ) 2 , CCH, CO 2 CH 3 , tBu,
17. The compound, deuterated derivative, or salt of claim 1 , wherein o is 0.
18. The compound, deuterated derivative, or salt of claim 1 , wherein o is 1.
19. The compound, deuterated derivative, or salt of claim 1 , wherein n is 0.
20. The compound, deuterated derivative, or salt of claim 1 , wherein n is 1.
21. The compound, deuterated derivative, or salt of claim 1 , wherein n is 2.
22. The compound, deuterated derivative, or salt of claim 1 , wherein p is 0.
23. The compound, deuterated derivative, or salt of claim 1 , wherein p is 1.
24. The compound, deuterated derivative, or salt of claim 1 , wherein p is 2.
25. The compound, deuterated derivative, or salt of claim 1 , wherein ring B is phenyl.
26. The compound, deuterated derivative, or salt of claim 1 , wherein ring B and ring C are phenyl.
27. A compound selected from:
deuterated derivatives thereof, and pharmaceutically acceptable salts of the foregoing.
28. A pharmaceutical composition comprising the compound, deuterated derivative, or salt of claim 1 and a pharmaceutically acceptable carrier.
29. The pharmaceutical composition of claim 28 , further comprising one or more additional therapeutic agent(s).
30. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.
31. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises
or pharmaceutically acceptable salt thereof.
32. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises
or pharmaceutically acceptable salt thereof.
33. The pharmaceutical composition of claim 29 , wherein the one or more additional therapeutic agent(s) comprises
or pharmaceutically acceptable salts thereof.
34. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the compound, deuterated derivative, or salt of claim 1 .
35. The method of claim 34 , further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the compound, deuterated derivative, or salt of claim 1 .
36. The method of claim 35 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.
37. The method of claim 35 , wherein the one or more additional therapeutic agent(s) comprises
or a pharmaceutically acceptable salt thereof.
38. The method of claim 35 , wherein the one or more additional therapeutic agent(s) comprises
or a pharmaceutically acceptable salt thereof.
39. The method of claim 34 , wherein the patient is homozygous in the ΔF508 CFTR mutation.
40. The method of claim 34 , wherein the patient is heterozygous in the ΔF508 CFTR mutation.
41. A method of treating cystic fibrosis in a patient comprising administering to the patient an effective amount of the pharmaceutical composition of claim 28 .
42. The method of claim 41 , further comprising administering to the patient one or more additional therapeutic agent(s) prior to, concurrent with, or subsequent to the pharmaceutical composition.
43. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises a CFTR modulator.
44. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises
or a pharmaceutically acceptable salt thereof.
45. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises
or a pharmaceutically acceptable salt thereof.
46. The method of claim 42 , wherein the one or more additional therapeutic agent(s) comprises
or pharmaceutically acceptable salts thereof.Cited by (0)
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